Background

GM-CSF leukine, aka sargramostim is a synthetic form of the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor. It is a 127 amino acid glycoprotein produced by recombinant DNA technology in yeast. Sargramostim stimulates the innate immune system. It is FDA-approved for regenerating neutrophils, monocytes, and macrophages after bone marrow transplants and in conjunction with treatment for several types of leukemia. Sargramostim is also used for treating neutropenia, a condition of dangerously low white-blood-cell counts. Sargramostim is not to be confused with filgrastim, a recombinant form of the related granulocyte colony-stimulating factor (G-CSF).

The rationale for evaluating sargramostim in Alzheimer's is that it might increase phagocytosis of pathogenic protein deposits by bone marrow-derived macrophages or brain-resident microglia, and that it might also stimulate other neuroprotective innate immunity processes. GM-CSF was reported to activate microglia in response to amyloid pathology without also augmenting microglial release of pro-inflammatory cytokines, as is seen in response to other, closely related neurotrophic factors (Murphy et al., 1998).

In transgenic mouse models of Alzheimer's disease, GM-CSF was reported to reduce amyloid pathology, improve cognition, and increase the number of microglia (Boyd et al., 2010). However, contradictory findings exist, as well (Manczak et al, 2009).

Both GM-CSF and its receptor appear to be expressed in aging human brains, both in controls and in people with Alzheimer's (Ridwan et al., 2012). Analysis of archived neuropsychology data from 19 patients who had received sagramostim as part of their supportive care for bone-marrow transplantation reported a cognitive benefit (Jim et al., 2012).

Findings

In 2011, a Phase 2 randomized study at the University of Colorado, Denver, and the Byrd Alzheimer's Institute of the University of Southern Florida, Tampa, started enrolling 40 patients with mild to moderate Alzheimer's disease to evaluate a three-week course of GM-CSF Leukine (250 microg/m2 per day) or placebo injected under the skin for five days each week. Tolerability is the primary outcome, to be monitored for six months. Various cognitive tests will be performed for up to six months after treatment as a secondary outcome. This study is set to complete in December 2017.

At the 2017 AAIC, investigators presented interim data on 32 participants, 13 on drug and 19 on placebo (see Aug 2017 conference). Patients were examined at baseline, at the end of the trial, and 45 and 90 days later, for safety and with cognitive and functional tests. Those in the treatment arm had an average MMSE score of 16.46 at baseline, versus 20.63 for those on placebo, a significant difference; ADL scores were also lower—54.61 for the treatment group and 63.16 for placebo.

GM-CSF Leukine seemed well-tolerated, with no serious adverse events reported and no signs of ARIA. Patients on drug scored about 1.5 points higher in MMSE than at baseline; placebo scores stayed unchanged. ADL score rose about 1.5 points in the treatment group at 3 weeks, but then fell similarly in treatment and placebo arms, respectively. No differences were reported between the two groups at later time points. No significant difference emerged at any time between treatment and placebo arms on the ADAS-Cog, CDR-sb or MOHS tests.

In 2013, the National Institute on Aging awarded funding for a Phase 2 trial to be conducted by Sanofi Aventis to evaluate sargramostim for its ability to clear amyloid deposits and affect cognition in patients with mild cognitive impairment (see Feb 2014 news). This study started in November 2016 and anticipated enrolling 30 people 40 or older who meet NIA-AA criteria for MCI due to AD and have a positive amyloid PET scan. This study was to evaluate a six-month course of subcutaneous injection of sargramostim or placebo for reduction of brain amyloid as measured by change in florbetabir retention. Secondary outcome measures were to include safety, CSF analysis, MRI to look for ARIA, and measurement of antibodies against sargramostim. This study was to be conducted in Houston but was withdrawn prior to enrollment due to slow recruitment.